UBC scientists fight disease molecule by molecule

Vanessa Auld and B. Brett Finlay fight disease one molecule at
a time.

The UBC scientists have received $275,000 US each from the Howard
Hughes Medical Institute to further research into the genesis of
nerve disorders and bacterial infections –innovative work combining
genetics, biochemistry and molecular and cell biology.

Finlay, a professor in UBC’s Biotechnology Laboratory, looks at
molecules which aid and abet the passage of disease-causing bacteria
in the human body. His focus has been on salmonella and Eschericia
coli (E. coli), two bacterial strains which result in typhoid fever,
debilitating diarrhea and other gastro-intestinal diseases.

E. coli has traditionally been treated through rehydration and
antibiotics but Finlay says bacteria are rapidly becoming resistant
to current medication.

Apart from preventing infections with new vaccines, Finlay seeks
to block the bacterium’s ability to operate in the body.

He describes salmonella, one of the leading causes of death among
HIV patients, and E. coli as having their own “little tool boxes”
to manipulate human cells.

E. coli, for instance, is called an adherent bacteria because it
sticks to the surface of human intestinal cells. Once in place,
the E. coli secretes special molecules from its tool box into the
host cell causing it to build a pedestal upon which the bacterium
sits.

“We know a lot of the molecules the bacteria use to build these
structures and if we make a mutation in one of those molecules,
the pedestals don’t get built and people don’t get sick,”says Finlay,
whose lab was one of the first to examine what happens to mammalian
host cells when they come in contact with bacteria.

Salmonella, as an intracellular bacteria, infects from the inside
of cells. It has a range of sophisticated molecular tools, the first
of which tricks human epithelial cells into engulfing it. Epithelial
cells line the nose, ears, mouth, stomach and intestinal tract forming
a barrier, like Goretex, between the outside and the inside of the
body.

Once the bacteria break through the epithelial barrier of the intestine,
they hitch a ride inside phagocytes (another molecular trick) which
are designed to kill foreign particles entering the bloodstream.
The phagocytes transport the salmonella to the liver and spleen
where the bacteria grow and kill more host cells.

Finlay grows models of epithelial cell barriers in tissue culture
to determine how the molecular process works.

Finlay’s lab is collaborating with several pharmaceutical companies
to identify molecular compounds that will block these processes.
One project with the local firm INEX seeks to control salmonella
and other intracellular parasites by tricking cells into swallowing
capsules of existing antibiotics. This technology would enable drugs
to work from the inside out.

Auld, an assistant professor with the Dept. of Zoology, investigates
molecular interactions between the brain’s two basic cell types:
nerve cells (neurons) and glial cells. Breakdowns in these interactions
can lead to a variety of neurodegenerative diseases.

Auld’s research explores how glial cells and neurons develop together
in the peripheral nervous system (PNS) — the sensory and motor
system existing outside the brain and spinal cord.

There are about 100 billion neurons in the brain and up to 10 times
that number of glial cells offering physical and nutritional support.

Auld explains that neurons represent the body’s wiring and glia
provide the necessary insulation, or glial sheath, for that wiring.
When the nervous system is setting up, glia can act as guideposts
or highways to make sure nerves go to the right places.

Once the nervous system is established, the glial sheath acts as
a both a protectant against short circuits and an air conditioner,
cleaning up residual ions or neurotransmittors left over from electrical
firings between neurons.

“To serve and protect, that’s their role,” says Auld, who uses
the fruit fly, Drosophila melanogaster, as the model to analyze
glial/neuron interactions.

In 1991, Auld discovered gliotactin, a gene specific to glial cells
expressed in the fruit fly’s embryonic PNS.

Gliotactin mediates the interaction between neurons and glial cells
by setting up a barrier or membrane between the blood system and
the nervous system. This so-called blood-brain barrier insulates
and protects the nerves.

Mutations in the gliotactin protein lead to paralysis in fruit
flies as the gene plays an essential role in establishing the glial
wrapping of the PNS.

Auld will use the Howard Hughes grant to look for mutants or new
genes that affect the development of glia and their interactions
with the nervous system. The process involves isolating new mutations
in Drosophila and looking for defects that involve glia.

“We’ll be looking for anything that effects how the glia are positioned,
how they migrate, how they wrap the neuron and anything that disrupts
this development,” she says. “At the molecular level, this would
show up in a gene.”

Auld’s long-range plans are to use the fruit fly as a springboard
to discovering the same genes in vertebrate systems. She says that
many genes important to vertebrate development were originally discovered
in Drosophila.

Finlay and Auld are among 20 Canadians named International Research
Scholars of the Howard Hughes Medical Institute.

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